View source for GPR84

{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
'''Probable G-protein coupled receptor 84''' is a [[protein]] that in humans is encoded by the ''GPR84'' [[gene]].<ref name="pmid11273702">{{cite journal | vauthors = Wittenberger T, Schaller HC, Hellebrand S | title = An expressed sequence tag (EST) data mining strategy succeeding in the discovery of new G-protein coupled receptors | journal = Journal of Molecular Biology | volume = 307 | issue = 3 | pages = 799–813 | date = March 2001 | pmid = 11273702 | doi = 10.1006/jmbi.2001.4520 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: GPR84 G protein-coupled receptor 84| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=53831}}</ref>

== Discovery ==

GPR84 (EX33) was described practically in the same time by two groups. One was the group of Timo Wittenberger in the Zentrum fur Molekulare Neurobiologie, Hamburg, Germany (Wittenberg T. et al.) and the other was the group of Gabor Jarai in Novartis Horsham Research Centre, Horsham, United Kingdom. In their papers they described the sequence and expression profile of five new members of GPC receptor family. One among them was GPR84 which represents a unique GPCR sub-family so far.

== Gene ==

Hgpr84 locates to chromosome 12q13.13, and its coding sequence is not interrupted by introns.<ref name="pmid11273702"/>

== Protein ==

The human and the murine GPR84 ORFs both encode proteins of 396 amino acid residues length with 85% identity and are therefore considered as orthologs.<ref name="pmid11273702"/> The hgpr84 was found by Northern blot analysis as a transcript of about 1.5 kb in brain, heart, muscle, colon, thymus, spleen, kidney, liver, intestine, placenta, lung, and leukocytes. In addition, a 1.2 kb transcript in heart and a strong band at 1.3 kb in muscle were detected. A Northern blot from different brain regions revealed strongest expression of the 1.5 kb transcript in the medulla and the spinal cord. Somewhat less transcript was found in the substantia nigra, thalamus, and the corpus callosum. The 1.5 kb band was also visible in other brain regions, but at very low levels. EST clones corresponding to hgpr84 were from B cells (leukemia), neuroendocrine lung as well as in microglial cells<ref name="Bouchard_2007">{{cite journal | vauthors = Bouchard C, Pagé J, Bédard A, Tremblay P, Vallières L | title = G protein-coupled receptor 84, a microglia-associated protein expressed in neuroinflammatory conditions | journal = Glia | volume = 55 | issue = 8 | pages = 790–800 | date = June 2007 | pmid = 17390309 | doi = 10.1002/glia.20506 | s2cid = 5626893 }}</ref> and adipocytes.<ref name="Nagasaki_2012">{{cite journal | vauthors = Nagasaki H, Kondo T, Fuchigami M, Hashimoto H, Sugimura Y, Ozaki N, Arima H, Ota A, Oiso Y, Hamada Y | display-authors = 6 | title = Inflammatory changes in adipose tissue enhance expression of GPR84, a medium-chain fatty acid receptor: TNFα enhances GPR84 expression in adipocytes | journal = FEBS Letters | volume = 586 | issue = 4 | pages = 368–72 | date = February 2012 | pmid = 22245676 | doi = 10.1016/j.febslet.2012.01.001 | s2cid = 10707457 | doi-access = free }}</ref> A more detailed description of expression profile can be found in www.genecards.org. The resting expression of GPR84 is usually low but it is highly inducible in inflammation. Its expression on neutrophils can be increased with [[lipopolysaccharide|LPS]] stimulation and reduced with [[GM-CSF]] stimulation. The LPS-induced upregulation of GPR84 was not sensitive to dexamathasone pretreatment. There was also a GPR84 downregulation in dentritic cell derived from FcRgamma chain KO mice.<ref name="urlopenaccess.leidenuniv.nl">{{cite thesis |url=https://openaccess.leidenuniv.nl/bitstream/handle/1887/16177/05.pdf?sequence=11 |title=FcgR Ligation on Dendritic Cells induces Broad Immune Response Gene Signature Tightly Regulated by FcgRIIb |author1=van Montfoort N |author2=‘t Hoen PAC |author3=Camps M |author4=Melief CJM |author5=Ossendorp F |author6=Verbeek JS |date=25 November 2010 |publisher=Leiden University |archive-date=3 March 2016 |access-date=15 January 2013 |archive-url=https://web.archive.org/web/20160303225604/https://openaccess.leidenuniv.nl/bitstream/handle/1887/16177/05.pdf?sequence=11 |url-status=live }}</ref> In microglial cells, the GPR84 induction with [[interleukin-1]] (IL-1) and [[tumor necrosis factor α]] (TNFα) was also demonstrated.<ref name="Bouchard_2007"/> 24 h treatment with IL-1β also  induced 5.8 times increase in GPR84 expression on PBMC from healthy individuals.<!-- (Kathryn M. et al.) -->{{citation needed|date=January 2013}} . Transcriptional dynamics of human umbilical cord blood T helper cells cultured in absence and presence of cytokines promoting Th1 or Th2 differentiation was studies. It turned out that GPR84 belongs to the Th1 specific subset genes.<ref name="pmid23110343">{{cite journal | vauthors = Aijö T, Edelman SM, Lönnberg T, Larjo A, Kallionpää H, Tuomela S, Engström E, Lahesmaa R, Lähdesmäki H | display-authors = 6 | title = An integrative computational systems biology approach identifies differentially regulated dynamic transcriptome signatures which drive the initiation of human T helper cell differentiation | journal = BMC Genomics | volume = 13 | pages = 572 | date = October 2012 | pmid = 23110343 | pmc = 3526425 | doi = 10.1186/1471-2164-13-572 | doi-access = free }}</ref> While another publication suggests that GPR84 is rather a CCL1 related Th2 type gene.<ref name="pmid22413885">{{cite journal | vauthors = Smeets RL, Fleuren WW, He X, Vink PM, Wijnands F, Gorecka M, Klop H, Bauerschmidt S, Garritsen A, Koenen HJ, Joosten I, Boots AM, Alkema W | display-authors = 6 | title = Molecular pathway profiling of T lymphocyte signal transduction pathways; Th1 and Th2 genomic fingerprints are defined by TCR and CD28-mediated signaling | journal = BMC Immunology | volume = 13 | pages = 12 | date = March 2012 | pmid = 22413885 | pmc = 3355027 | doi = 10.1186/1471-2172-13-12 | doi-access = free }}</ref>

GPR84 was also upregulated on both macrophages and neutrophyl granulocytes after [[Lipopolysaccharide|LPS]] stimulation.<ref name="pmid18442421">{{cite journal | vauthors = Lattin JE, Schroder K, Su AI, Walker JR, Zhang J, Wiltshire T, Saijo K, Glass CK, Hume DA, Kellie S, Sweet MJ | display-authors = 6 | title = Expression analysis of G Protein-Coupled Receptors in mouse macrophages | journal = Immunome Research | volume = 4 | pages = 5 | date = April 2008 | pmid = 18442421 | pmc = 2394514 | doi = 10.1186/1745-7580-4-5 | doi-access = free }}</ref> Not only [[Lipopolysaccharide|LPS]] challenge but [[Staphylococcal Enterotoxin B|Staphylococcus enterotoxin B]]  was sufficient to cause a 50 times increase in GPR84 expression on isolated human [[leukocyte]]s stimulated with compared to the expression of naive leukocytes.<ref name="pmid16878882">{{cite journal | vauthors = Sethu P, Moldawer LL, Mindrinos MN, Scumpia PO, Tannahill CL, Wilhelmy J, Efron PA, Brownstein BH, Tompkins RG, Toner M | display-authors = 6 | title = Microfluidic isolation of leukocytes from whole blood for phenotype and gene expression analysis | journal = Analytical Chemistry | volume = 78 | issue = 15 | pages = 5453–61 | date = August 2006 | pmid = 16878882 | doi = 10.1021/ac060140c }}</ref> A viral infection following Japanese encephalitis virus infection also increased GPR84 expression by 2–4.5% in the mice brain.<ref name="pmid21371334">{{cite journal | vauthors = Gupta N, Rao PV | title = Transcriptomic profile of host response in Japanese encephalitis virus infection | journal = Virology Journal | volume = 8 | pages = 92 | date = March 2011 | pmid = 21371334 | pmc = 3058095 | doi = 10.1186/1743-422X-8-92 | doi-access = free }}</ref>

Ablating [[lysosomal lipase|lysosomal acid lipase]] (Lal-/-) in mice led to aberrant expansion of [[myeloid]]-derived suppressive cells (MDSCs) (>40% in the blood, and >70% in the bone marrow) that arise from dysregulated production of myeloid progenitor cells in the bone marrow. Ly6G + MDSCs in Lal-/- mice show strong immunosuppression on T cells, which contributes to impaired T cell proliferation and function in vivo. GPR84 was 9.1 fold upregulated in the MDSCs of Lal-/- mice. GPR84 is normally expressed at low levels in myeloid cells and can be induced in vitro by stimulating macrophage or microglial cells with LPS, TNFα, or PMA. Elevated expression of GPR84 was also observed during the demyelination phase of the reversible Cuprizone-Induced Demyelinating Disease  mouse model. Finally, it has also shown that GPR84 expression is increased in both the normal appearing white matter and plaque in brains from human Multiple Sclerosis patients. Expression of GPR84 increases in mouse whole brain samples from [[experimental autoimmune encephalomyelitis]] before the onset of clinical disease.<ref name = "Gray">{{cite conference |vauthors=Gray JC, Potthoff B, Beckmann H, Kayser F, Escobar S, Mozaffarian A, Arnett HA, Kirchner J, Wang S | title = GPR84, a receptor expressed on myeloid cells and a potential target for treatment of Multiple Sclerosis | conference = Program#/Poster#: 824.26/D5}}</ref> In cultured microglia in response to simulated blast overpressure the expression of GPR84 was increased 2.9 fold.<ref name="pmid22698585">{{cite journal | vauthors = Kane MJ, Angoa-Pérez M, Francescutti DM, Sykes CE, Briggs DI, Leung LY, VandeVord PJ, Kuhn DM | display-authors = 6 | title = Altered gene expression in cultured microglia in response to simulated blast overpressure: possible role of pulse duration | journal = Neuroscience Letters | volume = 522 | issue = 1 | pages = 47–51 | date = July 2012 | pmid = 22698585 | pmc = 3396767 | doi = 10.1016/j.neulet.2012.06.012 }}</ref> In ageing TgSwe mice were subjected to traumatic brain injury GPR84 was upregulated by 6.3 fold.<ref name="pmid20374285">{{cite journal | vauthors = Israelsson C, Bengtsson H, Lobell A, Nilsson LN, Kylberg A, Isaksson M, Wootz H, Lannfelt L, Kullander K, Hillered L, Ebendal T | display-authors = 6 | title = Appearance of Cxcl10-expressing cell clusters is common for traumatic brain injury and neurodegenerative disorders | journal = The European Journal of Neuroscience | volume = 31 | issue = 5 | pages = 852–63 | date = March 2010 | pmid = 20374285 | doi = 10.1111/j.1460-9568.2010.07105.x | s2cid = 24061159 }}</ref> GPR84 expression was increased by 49.9 times in M1 type macrophages isolated from aortic atherosclerotic lesions of LDLR-/- mice were fed a western diet.<ref name="pmid20651288">{{cite journal | vauthors = Kadl A, Meher AK, Sharma PR, Lee MY, Doran AC, Johnstone SR, Elliott MR, Gruber F, Han J, Chen W, Kensler T, Ravichandran KS, Isakson BE, Wamhoff BR, Leitinger N | display-authors = 6 | title = Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2 | journal = Circulation Research | volume = 107 | issue = 6 | pages = 737–46 | date = September 2010 | pmid = 20651288 | pmc = 2941538 | doi = 10.1161/CIRCRESAHA.109.215715 }}</ref> GPR84 is important in regulating the expression of cytokines: CD4+ T cells from GPR84-/- mice show increase IL-4 secretion in the presence of anti-CD3 and anti-CD28 antibodies;<ref name="pmid15993493">{{cite journal | vauthors = Venkataraman C, Kuo F | title = The G-protein coupled receptor, GPR84 regulates IL-4 production by T lymphocytes in response to CD3 crosslinking | journal = Immunology Letters | volume = 101 | issue = 2 | pages = 144–53 | date = November 2005 | pmid = 15993493 | doi = 10.1016/j.imlet.2005.05.010 }}</ref> GPR84 potentiates LPS-induced IL12p40 secretion in RAW264.7 cells.<ref name="Wang_2006">{{cite journal | vauthors = Wang J, Wu X, Simonavicius N, Tian H, Ling L | title = Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84 | journal = The Journal of Biological Chemistry | volume = 281 | issue = 45 | pages = 34457–64 | date = November 2006 | pmid = 16966319 | doi = 10.1074/jbc.M608019200 | doi-access = free }}</ref>
Recent work by Nagasaki et al. explored 3T3-L1 adipocytes cocultured with RAW264.7 cells to examine this potential interaction.<ref name="Nagasaki_2012"/> RAW264.7 coculture increases GPR84 expression in 3T3-L1 adipocytes, and incubation with capric acid can inhibit TNFα-induced adiponectin release. Adiponectin regulates many metabolic processes associated with glucose and fatty acids, including insulin sensitivity and lipid breakdown. Furthermore, a high-fat diet can increase GPR84 expression. The authors suggest that GPR84 may explain the relationship between diabetes and obesity. As adipocytes release fatty acids in the presence of macrophages, the loop of increased GPR84 expression and its stimulation prevent the release of regulating hormones. The work on GPR84 is still very early and needs to be expanded in the context of pathophysiology and immune regulation. Some people presume the role of GPR84 in food intake too. GPR84 is expressed in the gastric corpus mucosa and this receptor can be an important luminal sensors of food intake and are most likely expressed on entero-endocrine cells, where it stimulates the release of peptide hormones including incretins glucagon-like peptide (GLP) 1 and 2.<ref name="pmid21177383">{{cite journal | vauthors = Goebel M, Stengel A, Lambrecht NW, Sachs G | title = Selective gene expression by rat gastric corpus epithelium | journal = Physiological Genomics | volume = 43 | issue = 5 | pages = 237–54 | date = March 2011 | pmid = 21177383 | pmc = 3068518 | doi = 10.1152/physiolgenomics.00193.2010 }}</ref>

== Ligands ==

The ligands for GPR84 suggest also a relationship between inflammation and fatty acid sensing or regulation. Medium-chain free fatty acid (FFA) with carbon chain lengths of C9 to C14. Capric acid (C10:0), undecanoic acid (C11:0) and lauric acid (C12:0) are the most potent<ref name="Wang_2006"/> described endogeneous agonists of GPR84. Not activated by short-chain and long-chain saturated and unsaturated FFAs induced in monocytes/macrophages by LPS. In addition, the activation of GPR84 in monocytes/macrophages amplifies LPS stimulated IL-12 p40 production in a concentration dependent manner.<ref name="Wang_2006"/> IL-12 plays an important role in promoting cell mediated immunity to eradicate pathogens by inducing and maintaining T helper 1 responses and inhibiting T helper 2 responses.<ref name="Wang_2006"/> Medium chain FFAs inhibited forskolin-induced cAMP production and stimulated [35S]GTPgammaS binding in a GPR84-dependent manner. The EC50 values for medium-chain FFAs capric acid, undecanoic acid, and lauric acid at GPR84 (4, 8, and 9 mM, respectively, in the cAMP assay). These results suggest that GPR84 activation by medium-chain FFAs is coupled to a pertussis toxin-sensitive Gi/o pathway.  Besides medium-chain FFAs diindolylmethane was also described as GPR84 agonist.<ref name="Wang_2006"/> However, the target selectivity of this molecule is also questionable because diindolylmethane is an aryl hydrocarbon receptor modulator, too.<ref name="pmid22592002">{{cite journal | vauthors = Yin XF, Chen J, Mao W, Wang YH, Chen MH | title = A selective aryl hydrocarbon receptor modulator 3,3'-Diindolylmethane inhibits gastric cancer cell growth | journal = Journal of Experimental & Clinical Cancer Research | volume = 31 | pages = 46 | date = May 2012 | issue = 1 | pmid = 22592002 | pmc = 3403951 | doi = 10.1186/1756-9966-31-46 | doi-access = free }}</ref> The patent literature mentions that besides medium chain FFAs other substances as  2,5-Dihydroxy-3-undecyl(1,4)benzoquinon, Icosa-5,8,11,14-tetraynoic acid and 5S,6R-Dihydroxy-icosa-7,9,11,14-tetraenoic acid (5S,6RdiHETE) are also ligands of GPR84.<ref name = "WO2007027661">{{ cite patent | country = WO | number = 2007027661 | status = application | title = Human G protein-coupled receptor and modulators thereof for the treatment of atherosclerosis and atherosclerotic disease and for the treatment of conditions related to MCP-1 expression  | pubdate = 2007-08-03 | fdate = 2005-08-29 | pridate = | inventor = Hakak Y, Unett DJ, Gatlin J, Liaw CW | assign1 = Arena Pharmaceuticals }}</ref> These two latest molecules say against the statement that long chain FFAs are not ligands of GPR84. Based on these results it is probable that besides medium chain FFAs some long chain FFAs can also be endogeneous ligands of GPR84. Further work is needed to confirm this hypothesis.

===Classification of GPR84===
Based on its binding and activation by medium-chain fatty acids, GPR84 has been recognized as a possible member of the [[free fatty acid receptor]] family.<ref name="pmid31105530">{{cite journal | vauthors = Falomir-Lockhart LJ, Cavazzutti GF, Giménez E, Toscani AM | title = Fatty Acid Signaling Mechanisms in Neural Cells: Fatty Acid Receptors | journal = Frontiers in Cellular Neuroscience | volume = 13 | issue = | pages = 162 | date = 2019 | pmid = 31105530 | pmc = 6491900 | doi = 10.3389/fncel.2019.00162 | url =  | doi-access = free }}</ref> However, GPR84 has not yet been given a FFAR designation possibly because capric acid, the most potent medium-chain fatty acid in activating GPR44, requires high concentrations (e.g., in the micromolar range) to do so. This consideration supports the need to search for other naturally-occurring agents that are more potent than caproic acid in activating this receptor.<ref name="pmid33001759">{{cite journal | vauthors = Luscombe VB, Lucy D, Bataille CJ, Russell AJ, Greaves DR | title = 20 Years an Orphan: Is GPR84 a Plausible Medium-Chain Fatty Acid-Sensing Receptor? | journal = DNA and Cell Biology | volume = 39 | issue = 11 | pages = 1926–1937 | date = November 2020 | pmid = 33001759 | doi = 10.1089/dna.2020.5846 | url = | doi-access = free }}</ref> In the meantime, GPR84 continues to be defined as an [[orphan receptor]], i.e., a receptor whose naturally occurring activator(s) is unclear.<ref name="pmid37533166">{{cite journal | vauthors = Aktar R, Rondinelli S, Peiris M | title = GPR84 in physiology-Many functions in many tissues | journal = British Journal of Pharmacology | volume = | issue = | pages = | date = August 2023 | pmid = 37533166 | doi = 10.1111/bph.16206 | url = | doi-access = free }}</ref>

== Major mediator in pathologic fibrotic pathways ==
GPR84 has been proposed to be a major mediator in pathologic fibrotic pathways.<ref name="A Newly Discovered Antifibrotic Pat">{{cite journal | vauthors = Gagnon L, Leduc M, Thibodeau JF, Zhang MZ, Grouix B, Sarra-Bournet F, Gagnon W, Hince K, Tremblay M, Geerts L, Kennedy CR, Hébert RL, Gutsol A, Holterman CE, Kamto E, Gervais L, Ouboudinar J, Richard J, Felton A, Laverdure A, Simard JC, Létourneau S, Cloutier MP, Leblond FA, Abbott SD, Penney C, Duceppe JS, Zacharie B, Dupuis J, Calderone A, Nguyen QT, Harris RC, Laurin P | display-authors = 6 | title = A Newly Discovered Antifibrotic Pathway Regulated by Two Fatty Acid Receptors: GPR40 and GPR84 | journal = The American Journal of Pathology | volume = 188 | issue = 5 | pages = 1132–1148 | date = May 2018 | pmid = 29454750 | doi = 10.1016/j.ajpath.2018.01.009 | doi-access = free }}</ref>

== Drugs under investigation ==
The molecule [[GLPG1205]] was under investigation by the [[Belgium|Belgian]] firm [[Galapagos NV]]. Its clinical effect against inflammatory disorders like [[inflammatory bowel disease]] was being investigated in 2015 in a Phase 2 Proof-of-Concept study in [[ulcerative colitis]] patients. The results published in January 2016 showed good pharmacokinetics, safety and tolerability. However, the target efficacy was not met. The development of GLPG1205 for ulcerative colitis was therefore stopped.<ref>{{cite web | title = Galapagos reports results with GLPG1205 in ulcerative colitis | date = 26 January 2016 | work = Galapagos | url = http://www.glpg.com/docs/view/56a70f4ad23cf-en | access-date = 24 February 2016 | archive-date = 1 March 2016 | archive-url = https://web.archive.org/web/20160301022748/http://www.glpg.com/docs/view/56a70f4ad23cf-en | url-status = dead }}</ref>

The molecule [[PBI-4050]] which inhibits GPR84 signaling is under investigation by the Canadian biotechnology firm Prometic. As of August 2018, it remains a promising drug targeting multiple type of fibrosis entering phase 3 clinical trials.<ref name="A Newly Discovered Antifibrotic Pat"/>

== References ==
{{reflist|32em}}

== Further reading ==
{{refbegin|32em}}
* {{cite journal | vauthors = Yousefi S, Cooper PR, Potter SL, Mueck B, Jarai G | title = Cloning and expression analysis of a novel G-protein-coupled receptor selectively expressed on granulocytes | journal = Journal of Leukocyte Biology | volume = 69 | issue = 6 | pages = 1045–52 | date = June 2001 | doi = 10.1189/jlb.69.6.1045 | pmid = 11404393 | s2cid = 8221937 | doi-access = free }}
* {{cite journal | vauthors = Takeda S, Kadowaki S, Haga T, Takaesu H, Mitaku S | title = Identification of G protein-coupled receptor genes from the human genome sequence | journal = FEBS Letters | volume = 520 | issue = 1–3 | pages = 97–101 | date = June 2002 | pmid = 12044878 | doi = 10.1016/S0014-5793(02)02775-8 | s2cid = 7116392 | doi-access =  }}
{{refend}}

{{G protein-coupled receptors}}

[[Category:G protein-coupled receptors]]